Gynaecomastia is characterised by an increased amount of breast tissue in males. A central issue in the evaluation of breast tissue in adult men is the separation of the normal from the abnormal. In autopsy data (Anderson J A & Groom J B, Acta Pathol Microbiol Immunol Scand 90:191, 1982) the incidence of active gynaecomastia is between 5% and 9%. However, it has been reported (Nutall F Q, J Clin Endocrinol Metab 48:338, 1979; Niewoehner C V & Nutall F Q, Am J Med 77:633, 1984) that approximately 40% of normal men and up to 70% of hospitalized men have palpable breast tissue. The reason for this discrepancy is not clear, but it may suggest that it can be difficult to distinguish true breast tissue from masses of adipose tissue without breast tissue (lipomastia). Alternatively, a true increase in the incidence of gynaecomastia may have taken place, or the autopsy data may underestimate the frequency of palpable breast tissue.
Histologically, early gynaecomastia is characterized by proliferation in the breast of both the fibroblastic stroma and the duct system, which elongates, buds, and duplicates. As gynaecomastia persists, progressive fibrosis and hyalization are associated with regression of epithelial proliferation. Eventually the number of ducts decreases. Resolution occurs by reduction in size and epithelial content with gradual disappearance of the ducts leaving hyaline bands that eventually disappears.
Growth of the breast in men, as in women, is mediated by estrogen and results from disturbances of the normal ratio of active androgen to estrogen in plasma or within the breast itself. Estradiol formation in the normal man occurs principally by the conversion of the circulating androgens to estrogens in peripheral tissues; the normal ratio of production of testosterone to estradiol in adult men is approximately 100:1 (6 mg versus 45 .mu.g), and the normal ratio of the two hormones in plasma is about 300:1. Feminization results when there is a significant decrease in this effective ratio as a result of diminished testosterone production or action, enhanced estrogen production, or both processes occurring simultaneously. The predominant manifestation of feminization in men is enlargement of the breast.
Enlargement of the male breast can occur as a normal physiologic phenomenon at certain stages of life or as the result of different pathologic conditions.
Physiologic gynaecomastia occur in newborns and adolescents as transient enlargements of the breast which normally disappears spontaneously within few weeks to years usually without leaving palpable changes. Gynaecomastia of aging occurs in otherwise healthy men. Forty percent or more of aged men have gynaecomastia. A likely explanation is the increase with age in the conversion of androgens to estrogens in the extraglandular tissues. Abnormal liver function or drug therapy may be contributing causes to gynaecomastia in such men.
Pathologic gynaecomastia can result from one of three basic mechanisms: deficiency in testosterone production or action (with or without a secondary increase in estrogen production), increase in estrogen production, or drugs.
When the primary cause of the overestrogenization can be identified and corrected, the breast enlargement usually subsides promptly and eventually disappears. However, in a number of cases no cause can be found and the gynaecomastia is called idiopathic or physiologic. These cases can in some persons at certain stages of life cause tremendous psychological disturbances. The cause in these cases is always an increased ratio of oestrogen/testosterone. There can be an increased risk of developing breast cancer under these circumstances. Surgery is undesirable in these otherwise healthy men. The most rational way to treat gynaecomastia would be to inhibit the underlying excess stimulation of breast tissue by endogenous oestrogen and to induce atrophy of the breast tissue.
Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783. Recently, centchroman as a racemate has been found potent as a cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).
U.S. Pat. No. 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts.
There remains today a need in the art for compositions and methods that are useful in the treatment or prophylaxis of idiopathic or physiologic gynaecomastia.
One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of idiopathic or physiologic gynaecomastia.